Featured
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Article
| Open AccessZBTB12 is a molecular barrier to dedifferentiation in human pluripotent stem cells
The metastability of stem cells requires a mechanism for actively blocking dedifferentiation to achieve successful differentiation. Here the authors show that ZBTB12 serves as a molecular barrier to dedifferentiation by repressing a primate-specific retrotransposon, HERVH.
- Dasol Han
- , Guojing Liu
- & Jiwon Jang
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Article
| Open AccessTranscriptional reprogramming of skeletal muscle stem cells by the niche environment
Aging leads to significant alteration in the gene expression of muscle stem cells. In vivo exposure of muscle stem cells from aged mice to a young niche environment restores the expression of a significant portion of age-altered genes in mice.
- Felicia Lazure
- , Rick Farouni
- & Vahab D. Soleimani
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Article
| Open AccessEpigenetic control of cellular crosstalk defines gastrointestinal organ fate and function
Mesenchymal-epithelial crosstalk plays a key role in gut development and stem cell homeostasis, though underlying mechanisms are still unclear. Here, the authors demonstrate that mesenchymal Polycomb Repressive Complex 2 controls niche signals for gut epithelial fate and growth.
- Ryan J. Smith
- , Minggao Liang
- & Tae-Hee Kim
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Article
| Open AccessB1 SINE-binding ZFP266 impedes mouse iPSC generation through suppression of chromatin opening mediated by reprogramming factors
Induced pluripotent stem cell (iPSC) reprogramming is inherently inefficient. Here the authors identify 24 reprogramming roadblock genes through a CRISPR/Cas9-mediated genome-wide knockout screen including a KRAB-ZFP Zfp266, knockout of which consistently enhances murine iPSC generation.
- Daniel F. Kaemena
- , Masahito Yoshihara
- & Keisuke Kaji
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Article
| Open AccessRedox-dependent Igfbp2 signaling controls Brca1 DNA damage response to govern neural stem cell fate
How reactive oxygen species regulate neuronal stem cell (NSC) behavior is poorly understood. Here, the authors report that Ncf1-dependent oxidation of Igfbp2 cystines represses DNA repair networks to regulate NSC self-renewal and cell fate decisions.
- Weam S. Shahin
- , Shima O. Ebed
- & John F. Engelhardt
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Article
| Open AccessEpigenetic and transcriptional regulations prime cell fate before division during human pluripotent stem cell differentiation
Many stem cells exhibit cell division coupled to differentiation, though the changes occurring between consecutive cell divisions have been difficult to study. Here they use synchronized hPSC culture to show that production of transcription factors and epigenetic changes are linked with cell division timing.
- Pedro Madrigal
- , Siwei Deng
- & Siim Pauklin
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Article
| Open AccessDNMT3B supports meso-endoderm differentiation from mouse embryonic stem cells
DNMT3B-dependent DNA methylation provides epigenetic priming at epiblast stage by methylating enhancers of ectodermal genes to ensure proper differentiation toward mesoendoderm tissues.
- Andrea Lauria
- , Guohua Meng
- & Salvatore Oliviero
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Article
| Open AccessRSL24D1 sustains steady-state ribosome biogenesis and pluripotency translational programs in embryonic stem cells
Pluripotency is coordinated at multiple levels of gene expression. Here the authors show that ribosome biogenesis is tightly regulated in embryonic stem cells (ESC) to control the translation of transcription and chromatin factors and dictate ESC fate.
- Sébastien Durand
- , Marion Bruelle
- & Mathieu Gabut
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Article
| Open AccessEpithelial disruption drives mesendoderm differentiation in human pluripotent stem cells by enabling TGF-β protein sensing
Fate specification in the mammalian epiblast rely on complex interactions between morphogens and tissue organization. Here, the authors highlight epithelial integrity as a key determinant of TGF-β activity and a mechanism guiding morphogen sensing and spatial cell fate change.
- Thomas Legier
- , Diane Rattier
- & Rosanna Dono
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Article
| Open AccessSensory nerve niche regulates mesenchymal stem cell homeostasis via FGF/mTOR/autophagy axis
Sensory nerves are important for tissue homeostasis. Here the authors show that sensory nerves contribute to Mesenchymal stem cell maintenance via FGF1, mTOR signaling and autophagy.
- Fei Pei
- , Li Ma
- & Yang Chai
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Article
| Open AccessWnt/β-catenin signalling is required for pole-specific chromatin remodeling during planarian regeneration
Any planarian fragment regenerates the missing head and tail in the proper end. Early activation of the Wnt/β-catenin signaling pathway changes the chromatin accessibility of the cells of the posterior-facing wound to regenerate a tail.
- Eudald Pascual-Carreras
- , Marta Marín-Barba
- & Teresa Adell
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Article
| Open AccessA genome-wide relay of signalling-responsive enhancers drives hematopoietic specification
Defining cis-regulatory elements is an important goal in understanding how gene expression is regulated. Here the authors show blood cell-specific gene expression is controlled by the action of thousands of differentiation stage-specific sets of cis-elements that respond to cytokine signals terminating at signaling responsive transcription factors.
- B. Edginton-White
- , A. Maytum
- & C. Bonifer
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Article
| Open AccessTherapeutic adenine base editing of human hematopoietic stem cells
Here, Liao and colleagues apply adenine base editor ABE8e and its PAM-less variant ABE8e-SpRY to β-thalassemia patient hematopoietic stem cells in the form of ribonucleoprotein complexes, resulting in efficient long-term editing and β-thalassemia alleviation.
- Jiaoyang Liao
- , Shuanghong Chen
- & Yuxuan Wu
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Article
| Open AccessLarge-scale perfused tissues via synthetic 3D soft microfluidics
Bioengineering live tissues has remained challenging due to limited nutrient exchange in the growing tissues. Here, the authors have developed micro-perfused 2-photon printing of 3D microfluidics, to engineer large-scale, viable and functional neural and hepatic 3D tissues.
- Sergei Grebenyuk
- , Abdel Rahman Abdel Fattah
- & Adrian Ranga
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Article
| Open AccessSenescent cells perturb intestinal stem cell differentiation through Ptk7 induced noncanonical Wnt and YAP signaling
Cellular senescence and associated secretory phenotype (SASP) are thought to contribute to aging and tissue dysfunction, though it is unclear how SASP impacts regeneration. Here the authors show that SASP factors impair regeneration, and that Ptk7 is a key secreted protein mediating that dysregulation.
- Jina Yun
- , Simon Hansen
- & Heinrich Jasper
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Perspective
| Open AccessMolecular versatility during pluripotency progression
During development the embryo must balance lineage specification against the preservation of plasticity using a limited molecular toolkit. In this Perspective, the authors propose Molecular Versatility as a paradigm for grouping molecular mechanisms that are repurposed through development to exert distinct functions.
- Giacomo Furlan
- , Aurélia Huyghe
- & Fabrice Lavial
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Article
| Open AccessAdipose tissue is a source of regenerative cells that augment the repair of skeletal muscle after injury
The dynamics of fibroadipogenic progenitors (FAPs) after muscle injury are crucial to ensure efficient regeneration. Here the authors show that a pool of FAPs originates from adipose tissue and are necessary for effective muscle regeneration.
- Quentin Sastourné-Arrey
- , Maxime Mathieu
- & Coralie Sengenès
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Article
| Open AccessEndogenous IL-1 receptor antagonist restricts healthy and malignant myeloproliferation
Enhanced IL-1β signaling pathway causes hematopoietic stem cell (HSC) to differentiate into myeloid cells and contributes to malignant hematopoiesis. Here the authors reveal that HSC differentiation is controlled by balanced levels of IL-1 receptor antagonist (IL-1rn) and IL-1β under steady-state, and that IL-1rn protects against pre-leukemic myelopoiesis by repressing IL-1β signaling.
- Alicia Villatoro
- , Vincent Cuminetti
- & Lorena Arranz
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Article
| Open AccessMultimodal monitoring of human cortical organoids implanted in mice reveal functional connection with visual cortex
Neuronal organoids derived from human induced pluripotent stem cells can be transplanted and integrated into the rodent cortex for the study of brain development and function. Here the authors demonstrate use of transparent graphene microelectrodes and two photon imaging for longitudinal, multimodal monitoring of functional connectivity between human iPSC derived neuronal organoids and the mouse cortex.
- Madison N. Wilson
- , Martin Thunemann
- & Duygu Kuzum
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Article
| Open AccessGlucose absorption drives cystogenesis in a human organoid-on-chip model of polycystic kidney disease
In polycystic kidney disease (PKD), fluid-filled cysts arise from tubules. Here the authors show that subjecting organoids to fluid shear stress in a PKD-on-a-chip microphysiological system promotes cyst expansion via an absorptive pathway.
- Sienna R. Li
- , Ramila E. Gulieva
- & Benjamin S. Freedman
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Article
| Open AccessMuscle 4EBP1 activation modifies the structure and function of the neuromuscular junction in mice
The group of Shih-Yin Tsai observed age-associated neuromuscular junction structural instability in male but not female mice which is driven by dysregulation of mTOR complex 1 activity. Genetic activation of the downstream phosphorylation target 4EBP1 in the muscle remodeled the neuromuscular junction and enhanced synaptic transmission.
- Seok-Ting J. Ang
- , Elisa M. Crombie
- & Shih-Yin Tsai
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Article
| Open AccessActivation of a transient progenitor state in the epicardium is required for zebrafish heart regeneration
The epicardium supports heart regeneration, though precisely how is unclear. Here the authors define an activated epicardial progenitor population as the source of essential cell types and paracrine factors for successful heart regeneration in zebrafish.
- Yu Xia
- , Sierra Duca
- & Jingli Cao
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Article
| Open AccessMyeloid cells promote interferon signaling-associated deterioration of the hematopoietic system
Innate and adaptive immune cells function in the homeostasis of haematopoietic stem cells (HSC). Here the authors show that myeloid cells are able to reduce the function of HSCs via interferon signaling through a neutrophil-NK cell dependent process.
- Jacqueline Feyen
- , Zhen Ping
- & Marc H. G. P. Raaijmakers
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Article
| Open AccessThe transcription factor DDIT3 is a potential driver of dyserythropoiesis in myelodysplastic syndromes
Myelodysplastic syndromes (MDS) are age-related pathologies in which alterations of hematopoietic stem cells lead to abnormal formation of blood cells. Here, the authors study the lesions that these cells undergo in aging and disease, characterizing a factor whose alteration in MDS leads to abnormal blood cell production.
- Nerea Berastegui
- , Marina Ainciburu
- & Felipe Prosper
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Article
| Open AccessBreast cancer prevention by short-term inhibition of TGFβ signaling
TGFβ signalling is reported to regulate hormone-responsive mammary epithelial progenitors that are associated with breast cancer risk. Here, the authors find that short-term TGFBR1 inhibition prevents tumour formation in rat breast cancer models and identify a TGFBR1 inhibition-responsive sub-population of mammary epithelial cells, which is associated with human breast cancer risk.
- Maša Alečković
- , Simona Cristea
- & Kornelia Polyak
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Article
| Open AccessCharacterization of an RNA binding protein interactome reveals a context-specific post-transcriptional landscape of MYC-amplified medulloblastoma
MYC amplification is an independent prognostic factor for the most aggressive subgroup (Group 3) of pediatric medulloblastoma (G3 MB). Here, the authors highlight the role of the RNA-binding protein, Musashi-1 (MSI1) in G3 MB and identify MSI1-bound targets sharing MYC associated pathways.
- Michelle M. Kameda-Smith
- , Helen Zhu
- & Sheila K. Singh
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Article
| Open AccessRetrotransposon instability dominates the acquired mutation landscape of mouse induced pluripotent stem cells
Retrotransposons are mobile genetic elements normally repressed by DNA methylation in differentiated cells. Here, the authors show that DNA hypomethylation in mouse induced pluripotent stem cells allows retrotransposons to jump, but this can be blocked with a reverse transcriptase inhibitor.
- Patricia Gerdes
- , Sue Mei Lim
- & Geoffrey J. Faulkner
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Article
| Open AccessBead-jet printing enabled sparse mesenchymal stem cell patterning augments skeletal muscle and hair follicle regeneration
Current mesenchymal stem cell (MSC) transplantation practices are limited by the loss or reduced performance of MSCs. Here the authors develop a bead-jet printer for intraoperative formulation and printing of MSCs-laden Matrigel beads to improve skeletal muscle and hair follicle regeneration.
- Yuanxiong Cao
- , Jiayi Tan
- & Shaohua Ma
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Article
| Open AccessNuclear localization of mitochondrial TCA cycle enzymes modulates pluripotency via histone acetylation
Cellular metabolism is important in pluripotency and cell fate regulation. Here, authors observe chromatin remodeling followed by TCA enzyme translocation from the mitochondria to the nucleus, demonstrating pluripotency regulation by mitochondria to nucleus retrograde signaling.
- Wei Li
- , Qi Long
- & Xingguo Liu
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Article
| Open AccessIL6 supports long-term expansion of hepatocytes in vitro
Hepatocytes are very difficult to expand in vitro. Here the authors discover that IL6 promotes long-term expansion (>30 passages) of primary mouse hepatocytes in vitro by converting the cells into hepatic progenitor cells, which maintain full capacity of differentiation into hepatocytes.
- Ren Guo
- , Mengmeng Jiang
- & Xin Xie
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Article
| Open AccessInactivation of LATS1/2 drives luminal-basal plasticity to initiate basal-like mammary carcinomas
LATS1/2 kinases are reported to be tumour suppressors in many cancers. Here the authors show that conditional deletion of LATS1/2 in the mature mouse luminal mammary epithelium leads to luminal-basal plasticity and development of basal-like carcinomas.
- Joseph G. Kern
- , Andrew M. Tilston-Lunel
- & Xaralabos Varelas
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Comment
| Open AccessGreater genetic diversity is needed in human pluripotent stem cell models
While there are a growing number of human pluripotent stem cell repositories, genetic diversity remains limited in most collections and studies. Here, we discuss the importance of incorporating diverse ancestries in these models to improve equity and accelerate biological discovery.
- Sulagna Ghosh
- , Ralda Nehme
- & Lindy E. Barrett
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Article
| Open AccessA soft and ultrasensitive force sensing diaphragm for probing cardiac organoids instantaneously and wirelessly
It is challenging to directly characterize mechanical properties of soft 3D cardiac organoids with current sensors. Here the authors report an electronic skin-based all-soft organoid-sensing system which can wirelessly monitor minute force profiles of cardiac organoids in real-time in-situ.
- Quanxia Lyu
- , Shu Gong
- & Wenlong Cheng
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Article
| Open AccessIntegration of single-cell transcriptomes and biological function reveals distinct behavioral patterns in bone marrow endothelium
Here Kim et al. show that primary BMECs can be maintained ex vivo as distinct sinusoidal- and arterial-like populations and that the presence of macrophages is critical to preserve their native transcriptomic profiles and functional heterogeneity.
- Young-Woong Kim
- , Greta Zara
- & Nadia Carlesso
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Article
| Open AccessPrimate-specific transposable elements shape transcriptional networks during human development
The human genome harbors more than 4.5 million transposable element (TE)-derived insertions, the result of recurrent waves of invasion and internal propagation. Here they show that TEs belonging to evolutionarily recent subfamilies go on to regulate later stages of human embryonic development, notably conditioning the expression of genes involved in gastrulation and early organogenesis.
- Julien Pontis
- , Cyril Pulver
- & Didier Trono
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Article
| Open AccessAlveolar cell fate selection and lifelong maintenance of AT2 cells by FGF signaling
Here the authors show that FGF signaling initiates alveolus development in mouse lung by inducing AT2 fate and a secondary signal for AT1 fate, and continuously maintains AT2 cells throughout life. FGF inhibition triggers immediate AT2 apoptosis and compensatory regeneration.
- Douglas G. Brownfield
- , Alex Diaz de Arce
- & Mark A. Krasnow
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Article
| Open AccessDepletion of CD206+ M2-like macrophages induces fibro-adipogenic progenitors activation and muscle regeneration
Muscle regeneration requires the contribution and communication of various different cell types. Here, Nawaz et al. show that CD206+ macrophages inhibit the secretion of the promyogenic factor follistatin by fibro-adipogenic progenitor cells, impeding myogenesis and muscle regeneration.
- Allah Nawaz
- , Muhammad Bilal
- & Kazuyuki Tobe
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Article
| Open AccessA Myb enhancer-guided analysis of basophil and mast cell differentiation
The transcription factor MYB has been shown to regulate haematopoietic stem cells but there could be lineage specific enhancers. Here, using lineage tracing and single cell sequencing the authors characterise a Myb −68 enhancer that regulates the differentiation of mast cells and basophils.
- Takayoshi Matsumura
- , Haruhito Totani
- & Toshio Suda
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Article
| Open AccessNorepinephrine transporter defects lead to sympathetic hyperactivity in Familial Dysautonomia models
Sympathetic neurons are affected in familial dysautonomia, a rare disease associated with a mutation in ELP1, but the mechanisms are not fully understood. Here the authors show, using neurons derived from participants with familial dysauotnomia, that spontaneous sympathetic neuron hyperactivity is observed and is associated with norepinephrine transporter deficits.
- Hsueh-Fu Wu
- , Wenxin Yu
- & Nadja Zeltner
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Article
| Open AccessCHD7 regulates otic lineage specification and hair cell differentiation in human inner ear organoids
Mutations in the chromatin remodeler CHD7 cause CHARGE syndrome, affecting development of several organs including the inner ear. Here, the authors recapitulated pathogenesis of this disease with human inner ear organoids and found that CHD7 is indispensable for proper otic lineage specification and hair cell differentiation.
- Jing Nie
- , Yoshitomo Ueda
- & Eri Hashino
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Article
| Open AccessCBP-HSF2 structural and functional interplay in Rubinstein-Taybi neurodevelopmental disorder
Rubinstein-Taybi syndrome (RSTS) is a neurodevelopmental disorder with unclear underlying mechanisms. Here, the authors unravel the contribution of a stress-responsive pathway to RSTS where impaired HSF2 acetylation, due to RSTS-associated CBP/EP300 mutations, alters the expression of neurodevelopmental players, in keeping with hallmarks of cell-cell adhesion defects.
- Aurélie de Thonel
- , Johanna K. Ahlskog
- & Valérie Mezger
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Article
| Open AccessHuman multilineage pro-epicardium/foregut organoids support the development of an epicardium/myocardium organoid
Stem cell models of organogenesis are a valuable tool for the study of human development, but often lack the context of tissue-tissue interaction. Here they generate human multi-lineage organoids comprising pro-epicardium, septum transversum, and liver bud, which they co-culture with heart organoids to generate a physiologically relevant model of organogenesis.
- Mariana A. Branco
- , Tiago P. Dias
- & Maria Margarida Diogo
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Article
| Open AccessProgrammable integrin and N-cadherin adhesive interactions modulate mechanosensing of mesenchymal stem cells by cofilin phosphorylation
Human mesenchymal stem cells differentiate in response to mechanical adhesive interactions in their microenvironment. Here, the authors develop a culture platform that can dynamically mimic the cell-cell and cell-extracellular matrix interactions associated with development and mesenchymal differentiation in vivo.
- Zheng Zhang
- , Baoyong Sha
- & Min Lin
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Article
| Open AccessCK2-mediated phosphorylation of SUZ12 promotes PRC2 function by stabilizing enzyme active site
Here the authors identify SUZ12 as a cellular substate of casein kinase 2 (CK2), and show this phosphorylation changes the active site structure of Polycomb repressive complex 2 (PRC2) and promotes PRC2 function in cell identity maintenance during stem cell differentiation.
- Lihu Gong
- , Xiuli Liu
- & Xin Liu
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Article
| Open AccessLamin A/C-dependent chromatin architecture safeguards naïve pluripotency to prevent aberrant cardiovascular cell fate and function
LMNA mutations cause severe heart dysfunction. Here the authors show that Lamin A/C plays a key role in 3D chromatin architecture in naïve pluripotent stem cells, which ensures proper cardiovascular cell fate and function, and shed light on the mechanisms involved in LMNA cardiomyopathies.
- Yinuo Wang
- , Adel Elsherbiny
- & Gergana Dobreva
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Article
| Open AccessBase-editing-mediated dissection of a γ-globin cis-regulatory element for the therapeutic reactivation of fetal hemoglobin expression
Antoniou and colleagues used base editing to generate a variety of mutations inducing γ-globin and rescue the β-hemoglobinopathy phenotype. This strategy was safe and effective in long-term repopulating hematopoietic stem/progenitor cells.
- Panagiotis Antoniou
- , Giulia Hardouin
- & Annarita Miccio
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Article
| Open AccessSexually dimorphic estrogen sensing in skeletal stem cells controls skeletal regeneration
How bone-related sexually dimorphic traits are regulated hasn’t been examined at the stem cell level. Here the authors show that skeletal stem cells (SSC), in female but not male mice, are directly controlled by estrogen signaling, which could be augmented to improve fracture repair.
- Tom W. Andrew
- , Lauren S. Koepke
- & Charles K. F. Chan
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Article
| Open AccessEya-controlled affinity between cell lineages drives tissue self-organization during Drosophila oogenesis
Oogenesis depends on close interaction between germ cells and the surrounding somatic niche. Here the authors demonstrate that Eya controls bilateral affinity at the germline-soma interface to generate self-organizing inter-lineage units that ensure oocyte maturation.
- Vanessa Weichselberger
- , Patrick Dondl
- & Anne-Kathrin Classen
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Article
| Open AccessThe type 1 diabetes gene TYK2 regulates β-cell development and its responses to interferon-α
The TYK2 gene is associated with development of type 1 diabetes. Here the authors show that TYK2 regulates β-cell development, but at the same time TYK2 inhibition in the islets prevents IFNα responses and enhances their survival against CD8+ T-cell cytotoxicity; representing a potent therapeutic target to halt T1D progression.
- Vikash Chandra
- , Hazem Ibrahim
- & Timo Otonkoski
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